ABSTRACT ? PROJECT 2 There are 2.5 million severe asthma patients in US. These patients are typically unresponsive, or poorly responsive to currently available asthma drugs. Therefore there is high unmet medical need for these patients. Several studies have suggested a central role for IL-17 (also called IL-17A) in severe asthma. Project 2's studies in the Program during Cycle I revealed the importance of IL-17 signaling pathways in the pathogenesis of asthma. The overall goal of Cycle II will focus on developing new therapeutic agents to block IL-17A pathway for the treatment of severe asthma. Project 2 was selected in 2015 to receive NCAI-CC support to begin to advance discoveries into novel therapies for severe asthma. Using IL-17R-deficient mice, Project 2 demonstrated the critical role of IL-17A signaling in High-Fat Diet-induced airway hyperreactivity and Aspergillus-induced animal model of severe asthma. Thus, Project 2 hypothesizes that the IL-17A pathway is an important target for the treatment of severe and steroid-resistant asthma. Through computer-aided virtual screening based on the crystal structure of IL-17RA/IL-17A complex, Project 2 has identified one small molecule lead compound (A18) that inhibits IL-17A binding to IL-17RA in in vitro biochemical assay, in IL-17A- induced gene expression in cultured cells and in preclinical studies, i.e. attenuation of IL-17A-dependent neutrophilia, airway inflammation, and airway hyper-reactivity. Project 2 has also developed a decoy peptide of Act1 (adaptor for IL-17R) to inhibit IL-17A intracellular signaling, and IL17A biomarkers that will facilitate the identification of patient populations responsive to IL-17A inhibitors. Project 2 aims to (1) further optimize the A18 structure for better bioactivities with drug-like properties for a 2nd generation of lead compound(s) and develop peptidomimetics based on the decoy peptides; (2) validate A18, A18 derivatives and peptidomimetics in IL-17A-induced pulmonary neutrophilia, HFD- and Aspergillus-induced severe asthma models in collaboration with Aronica's lab and the Animal Core (Dr. Asosingh); (3) partnering with Novartis, Project 2 will collaborate with Project 1 on defining the Biomarkers for IL-17A-targeted treatment. Additionally, Project 2 will interact with the regulatory experts through Core B for pre-IND advice from the FDA in order to submit the required data for an IND application to move the small molecule development candidate into the clinic. As part of the commercialization plan, Project 2 is enthusiastic to explore the possibility of developing the platform of small molecule and peptidomimetic strategy through the creation of a start-up in Cleveland. Core B will work with Project 2 to identify team members for the start-up with prior life sciences technology start-up experience in order to, raise capital to invest in de-risking the technology to make it more attractive for joint development with a pharma partner or to position the start-up as a competitive acquisition target.